Despite recent advances in biomarker identification, there remain fundamental gaps in the knowledge regarding the mechanisms, treatment and prevention of preeclampsia and related hypertensive disorders of pregnancy. The long-term goal is to better understand the pathophysiology of preeclampsia so that safe and appropriate therapies can be developed and implemented. The objective of this application is to determine the mechanisms by which exercise training safely lowers blood pressure during hypertensive disorders of pregnancy by utilizing the only animal model of preeclampsia that mimics the wide range of factors present in affected women. The central hypothesis for events following placental ischemia is that exercise training stimulates VEGF expression via AMP-activated protein kinase (AMPK) dependent mechanisms resulting in restoration of angiogenic balance, endothelial cell function, and normal blood pressure. The rationale for the proposed research is that identifying safe, effective treatments for preeclampsia will translate into reduced incidence and better management of hypertensive disorders of pregnancy and will directly benefit short- and long-term health outcomes of affected mothers and children. In addition, gaining a better understanding of mechanism linking exercise training to blood pressure control will have far reaching benefits in other patient populations including those with metabolic syndrome and cancer patients undergoing anti-angiogenic therapy. Guided by strong preliminary data, this hypothesis will be tested by pursuing three specific aims: 1) Identify exercise training as a non-pharmacologic method to improve angiogenic profile, lower blood pressure and restore endothelial function in RUPP hypertension; 2) Identify VEGF as a critical mediator of exercise-induced reductions of blood pressure during RUPP hypertension; 3) Identify AMPK activation as a critical event for exercise-induced restoration of angiogenic balance, vascular endothelial cell function, and reduction of blood pressure in RUPP hypertension. Under the first aim, an exercise training protocol which has been established as feasible in the applicants hands will be used to lower blood pressure in already proven animal model of preeclampsia. Under the second and third aims mechanisms by which blood pressure is lowered by exercise will be examined using gene delivery and pharmacological approaches in vivo combined with in vitro cell culture and tissue explant studies. The approach is innovative because it combines the use of a robust animal model of preeclampsia in which hypertension develops spontaneously after the onset of placental ischemia with in vitro methods to evaluate function and cellular mechanisms. The proposed research is significant because it will advance our understanding of the role of exercise as a treatment or preventative measure for hypertension during pregnancy and identify mechanisms that can also be exploited for the development of treatments of hypertension in a variety of settings. PUBLIC HEALTH RELEVANCE: The proposed research is critically important to public health because the development of preventative and treatment modalities for hypertensive disorders of pregnancy will have tremendous impacts on mother and child. The proposed research is relevant to the strategic plan of NHLBI and to the NIH's mission to develop fundamental knowledge about the nature and behavior of living systems and the application of that knowledge to enhance health, and reduce the burdens of illness.